Acetylene derivatives having mglur 5 antagonistic activity

ABSTRACT

The invention provides compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein n, A, R, R′, R″, R 0 , X and Y are as defined in the description, and their preparation. The compounds of formula I are useful as pharmaceuticals.

The present invention relates to novel acetylene derivatives, theirpreparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

More particularly the invention provides a compound of formula I

wherein

-   m is 0 or 1,-   n is 0 or 1 and-   A is hydroxy-   X is hydrogen and-   Y is hydrogen, or-   A forms a single bond with X or with Y;-   R₀ is hydrogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, trifluoromethyl, halogen,    cyano, nitro, —COOR₁ wherein R₁ is (C₁₋₄)alkyl or —COR₂ wherein R₂    is hydrogen or (C₁₋₄)alkyl, and-   R is —COR₃, —COOR₃, —CONR₄R₅ or —SO₂R₆, wherein R₃ is (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl or optionally substituted phenyl, 2-pyridyl or    2-thienyl, R₄ and R₅, independently, are hydrogen or (C₁₋₄)alkyl and    R₆ is (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl or optionally substituted    phenyl,-   R′ is hydrogen or (C₁₋₄)alkyl and-   R″ is hydrogen or (C₁₋₄)alkyl, or-   R′ and R″ together form a group —CH₂—(CH₂)_(p)—    -   wherein p is 0, 1 or 2, in which case one of n and p is        different from 0,        with the proviso that R₀ is different from hydrogen,        trifluoromethyl and methoxy when m is 1, n is 0, A is hydroxy, X        and Y are both hydrogen, R is COOEt and R′ and R″ together form        a group —(CH₂)₂—,        in free base or acid addition salt form.

On account of the asymmetrical carbon atoms present in the compounds offormula I and their salts, the compounds may exist in optically activeform or in form of mixtures of optical isomers, e.g. in form of racemicmixtures. All optical isomers and their mixtures including the racemicmixtures are part of the present invention.

In a further aspect, the invention provides a process for the productionof the compounds of formula I and their salts, which comprises the stepof

-   a) for the production of a compound of formula I wherein A is    hydroxy, reacting a compound of formula II

-   -   wherein m, n, R, R′ and R″ are as defined above, with a compound        of formula III

-   -   wherein R₀ is as defined above, or

-   b) for the production of a compound of formula I wherein A forms a    single bond with X or with Y, dehydrating a compound of formula I    wherein A is hydroxy,    and recovering the resulting compound of formula I in free base or    acid addition salt form.

The reaction of process a) can be effected according to conventionalmethods, e.g. as described in Examples 1 (step e), 2 (step d), 5 (stepb) and 8.

The dehydratation of process b) leads to a mixture of a compound offormula I wherein A forms a single bond with X and a compound of formulaI wherein A forms a single bond with Y, which are subsequently separatedaccording to conventional methods, e.g. as described in Examples 6, 9and 10.

A so obtained compound of formula I can be converted into anothercompound of formula I according to conventional methods, e.g, asdescribed in Examples i (steps f and g), 4 and 7.

Working up the reaction mixtures according to the above processes andpurification of the compounds thus obtained may be carried out inaccordance to known procedures.

Acid addition salts may be produced from the free bases in known manner,and vice versa.

Compounds of formula I in optically pure form can be obtained from thecorresponding racemates according to well-known procedures.Alternatively, optically pure starting materials can be used.

The starting materials of formulae II and III are known or may beobtained from known compounds, using conventional procedures.

Compounds of formula I obtained in accordance with the above-describedprocess can be converted into other compounds of formula I in customarymanner.

Resulting acid addition salts can be converted into other acid additionsalts or into the free bases in a manner known per se.

The compounds of formula I, including their acid addition salts, mayalso be obtained in the form of hydrates or may include the solvent usedfor crystallization.

Compounds of formula I and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties and are therefore useful aspharmaceuticals.

In particular, the agents of the invention exhibit a marked andselective modulating, especially antagonistic, action at humanmetabotropic glutamate receptors (mGluRs). This can be determined invitro for example at recombinant human metabotropic glutamate receptors,especially PLC-coupled subtypes thereof such as mGluR5, using differentprocedures like, for example, measurement of the inhibition of theagonist induced elevation of intracellular Ca²⁺ concentration inaccordance with L. P. Daggett et al., Neuropharm, Vol. 34, pages 871-886(1995), P. J. Flor at al., J. Neurochem, Vol. 67, pages 58-53 (1996) orby determination to what extent the agonist induced elevation of theinositol phosphate turnover is inhibited as described by T. Knoepfel etal., Eur. J. Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett etal., Neuropharm. Vol. 67, pages 58-83 (1996) and references citedtherein. Isolation and expression of human mGluR subtypes are describedin U.S. Pat. No. 5,521,297. Selected agents of the invention showIC₅₀values for the inhibition of the quisqualate-induced inositolphosphate turnover, measured in recombinant cells expressing hmGluR5a ofabout 1 nM to about 50 μM.

The agents of the invention are therefore useful in the treatment ofdisorders associated with irregularities of the glutamatergic signaltransmission, and of nervous system disorders mediated full or in partby mGluR5.

Disorders associated with irregularities of the glutamatergic signaltransmission are for example epilepsy, cerebral ischemias, especiallyacute ischemias, ischemic diseases of the eye, muscle spasms such aslocal or general spasticity and, in particular, convulsions or pain.

Nervous system disorders mediated full or in part by mGluR5 are forexample acute, traumatic and chronic degenerative processes of thenervous system, such as Parkinson's disease, senile dementia,Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosisand multiple sclerosis, psychiatric diseases such as schizophrenia andanxiety, depression, pain, itch and drug abuse, e,g, alcohol andnicotine abuse and cocaine use disorders.

The usefulness of the agents of the invention in the treatment of theabove-mentioned disorders can be confirmed in a range of standard testsincluding those indicated below.

Activity of the agents of the invention in anxiety can be demonstratedin standard models such as the stress-induced hyperthermia in mice [cf.A. Lecci et al., Psychopharmacol, 101, 255-261]. At doses of about 0.1to about 39 mg/kg p.o., the agents of the invention reverse thestress-induced hyperthermia.

At doses of about 4 to about 50 mg/kg p,o., the agents of the inventionshow reversal of Freund complete adjuvant (FCA) induced hyperalgesia[cf. J. Donnerer et al., Neuroscience 49, 693-698 (1992) and C. J.Woolf, Neuroscience 62, 327-331 (1994)].

For all the above mentioned indications, the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about 0.5to about 100 mg/kg animal body weight, in larger mammals, for examplehumans, an indicated daily dosage is in the range from about 5 to 1500mg, preferably about 10 to about 1000 mg of the compound convenientlyadministered in divided doses up to 4 times a day or in sustainedrelease form.

In accordance with the foregoing, the present invention also provides anagent of the invention for use as a pharmaceutical, e.g. in thetreatment of disorders associated with irregularities of theglutamatergic signal transmission, and of nervous system disordersmediated full or in part by mGluR5.

The invention also provides the use of an agent of the invention, in thetreatment of disorders associated with irregularities of theglutamatergic signal transmission, and of nervous system disordersmediated full or in part by mGluR5.

Furthermore the invention provides the use of an agent of the inventionfor the manufacture of a pharmaceutical composition designed for thetreatment of disorders associated with irregularities of theglutamatergic signal transmission, and of nervous system disordersmediated full or in part by mGluR5.

In a further aspect the invention relates to a method of treatingdisorders mediated full or in part by mGluR5, which method comprisesadministering to a warm-blooded organism in need of such treatment atherapeutically effective amount of an agent of the invention.

Moreover the invention relates to a pharmaceutical compositioncomprising an agent of the invention in association with at least onepharmaceutical carrier or diluent.

The pharmaceutical compositions according to the invention arecompositions for enteral, such as nasal, rectal or oral, or parenteral,such as intramuscular or intravenous, administration to warm-bloodedanimals (human beings and animals) that comprise an effective dose ofthe pharmacological active ingredient alone or together with asignificant amount of a pharmaceutically acceptable carrier. The dose ofthe active ingredient depends on the species of warm-blooded animal,body weight, age and individual condition, individual pharmacokineticdata, the disease to be treated and the mode of administration.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragoes, tablets or capsules.

The agents of the invention may alternatively be administered e.g,topically in the form of a cream, gel or the like, or by inhalation,e,g, in dry powder form.

Examples for compositions comprising an agent of the invention include,e.g, a solid dispersion, an aqueous solution, e,g, containing asolubilising agent, a microemulsion and a suspension of an agent of theinvention. The composition may be buffered to a pH in the range of e.g.from 3.5 to 9.5, by a suitable buffer.

The pharmaceutical compositions of the present invention are prepared ina manner known per as, for example by means of conventional dissolving,lyophilizing, mixing, granulating or confectioning processes.

The agents of the invention can be administered either alone, or incombination with other pharmaceutical agents effective in the treatmentof conditions mentioned above.

For the indication pain, the agents of this invention can be used incombination with analgesic agents (opiates) or with nonsteroidalanti-inflammatory drugs (NSAIDs) such as Rofecoxib (Vioxx®), Celecoxib(Celebrex®) or Lumiracoxib (Prexige®).

For the indication nicotine use disorders, the agents of the inventioncan be used in combination with bupropione (Zyban®).

The preferred agents of the invention include the (−)-(3aR, 4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acidmethyl ester in free base or pharmaceutically acceptable acid additionsalt form.

Said compound inhibits the quisqualate-induced inositol phosphateturnover in hmGlu5 expressing cells with an IC₅₀ concentration of 30 nM.With the same compound, a stress-induced hyperthermia of 0.92±0.09° C.was reduced to 0.56±0.06° C. at 0.1 mg/kg p.o., to 0.42±0.06° C. at 1mg/kg p.o. and to 0.18±0.05° C. at 10 mg/kg p.o. (p<0.001 in each case).

The following non-limiting Examples illustrate the invention.

EXAMPLE 1 (−)-(3aR, 4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acidmethyl eater

-   -   1,5,6,7-Tetrahydro-indol-4-one (38.4 g, 28.1 mmol),        di-tert-butyldicarbonate (66 g; 302 mmol) and potassium        tart-butylate (6 g; 62.5 mmol) in 1 l tetrahydrofuran are heated        under reflux for 2 h. After cooling, at room temperature the        reaction mixture is poured on brine (1 l) and extracted with        tert.-butylmethylether (4×600 ml). The combined organic phases        are dried over Na₂SO₄, filtered and evaporated in vacuo. 51 g of        yellowish oil are isolated and purified by column chromatography        on silica gel (600 g; eluent hexane/ethylacetate 8:2 v/v). 30.5        g (92%) of 1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic acid        tert.butyl ester as white crystals are isolated (mp 84-86° C.).    -   b) 1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic acid tert-butyl        ester (60 g; 255 mmol) and 15 g of 5% Pt on charcoal (given in        three portions of 5 g each; 24 h, 48, 72 h) in 1 l of methanol        are hydrogenated (1 bar) at room temperature under stirring for        92 h. The mixture is filtered and the solvent evaporated in        vacuo. The residual brownish oil is purified by chromatography        on silica gel to yield        (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid        tert-butyl ester as a yellowish oil (41.3 g; yield 67%).    -   c) To a solution of oxalylchloride (1.54 ml; 17.6 mmol) in THF        (320 ml) cooled to −60° C. a solution of DMSO (2.28 ml; 32 mmol)        in THF (32 ml) is added dropwise under stirring. After 5 min a        solution of        (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid        tert-butyl ester (3.96 g; 16.4 mmol) in THF (64 mil is added and        the reaction mixture stirred for 100 min at −60° C.        Triethylamine (11.2 ml; 80 mmol) is added and the cooling bath        removed and the reaction mixture stirred for further 60 min. The        reaction mixture is diluted with ethylacetate (1 l) and washed        with sat, NaHCO₃ (150 ml). The water phase is extracted with        ethylacetate (300 ml). The combined organic phases are dried        over Na₂SO₄, filtered and evaporated in vacuo. The residue is        purified by column chromatography on silica gel (150 g) and the        fractions containing the desired compound are collected and        evaporated in vacuo to yield        (3aRS,7aRS)-4-Oxo-octahydro-indole-1-carboxylic acid tert-butyl        ester (2.51 g; yield=65%).    -   d1) 4 g of (3aRS,7aRS)-4-oxo-octahydro-indole-1-carboxylic acid        tert-butyl ester are dissolved in 200 ml of hexane-ethanol 80:20        (v/v). This solution is injected via the pump on a 5 cm by 50 cm        Chiralpak AD column (Daicel Chemical Industries). The        chromatography is achieved at room temperature at a flow-rate of        100 ml/min and UV detection is performed at 210 nm. The mobile        phase consists of a mixture of hexane-ethanol 80:20 (v/v). Under        the applied chromatographic conditions, the (+)-enantiomer is        isolated from a first fraction collected between 11 and 18 min,        and the (−)enantiomer from a second fraction collected between        20 and 40 min. After 6 injections of a total of 27 g of        racemate, the fractions containing the corresponding enantiomers        are combined to yield 12.55 g of (+)-enantiomer and 12.23 g of        (+)-enantiomer, with an enantiomeric purity of 99% and 99.9%,        respectively. The enantiomeric: purity is determined on an        analytical Chiralpak AD column (0.4×25 cm); mobile phase,        hexane-ethanol 90:10 (v/v).        (−)-(3aR,7aR)-4-oxo-octahydro-indole-1-carboxylic acid        tert-butyl ester        ([α]_(D)=−111.6);—(+)-(3aS,7aS)-4-oxo-octahydro-indole-1-carboxylic        add ted-butyl ester ([α]_(D)=+105.2).    -   d2a) Alternatively        (−)-(3aR,7aR)-oxo-octahydro-indole-1-carboxylic acid tert-butyl        ester can be obtained via the following procedure:        -   To 11.76 g (47.16 mmol)            (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid            tert-butyl ester in 50 ml TBME and 30 g (34.8 mmol) vinyl            acetate, 0.5 g of immobilized lipase from Candida antarctica            (Novozyme 435) is added and the mixture is stirred at room            temperature for 24 h. After filtration of the mixture, the            solvent is removed and the obtained oily residue is purified            by flash chromatography. The acetate            (3aS,4R,7aS)-4-acetoxy-octahydro-indole-1-carboxylic acid            tert-butyl ester is isolated in 47% yield with an optical            purity of >99% (GC, [α]_(D) ²⁰=54.6° c=1, MeOH). The            recovered alcohol            (3aR,4S,7aR)-4-hydroxyoctahydro-indole-1-carboxylic acid            tert-butyl ester is obtained in 51% yield and >95% e.e. (GC,            [α]_(D) ²⁰=−41.3° c=1, MeOH). Further purification by Mae,            affords the alcohol with 99.5% purity and 99.5% e.e.    -   d2b) The alcohol        (3aR,4S,7aR)-4-hydroxy-actahydro-indole-1-carhoxylic acid        tert-butyl ester is oxidized to the ketone as described in        Example 1c) to yield        (−)-(3aR,7aR)-4-oxo-octahydro-indole-1-carboxylic acid        tert-butyl ester.    -   e) To a solution of 1-ethynyl-3-methyl-benzene (3.248 g; 28        mmol) THF (168 ml) cooled to −20° C., a solution of butyllithium        (17.5 ml; 28 mmol; 1.6M in hexane) is added. The reaction        mixture is stirred at −20° C., for 2 h then a solution of        (−)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester        (3.346 g; 14 mmol) THF (70 ml) is added and the reaction Mixture        further stirred at 0-5° C. After 2 h the reaction mixture is        diluted with ethylacetate (900 ml) and washed with sat. NaHCO₃        (2×90 ml). The aqueous phase is extracted with ethylacetate (400        ml). The combined organic phases are dried over Na₂SO₄, filtered        and evaporated in vacuo. The residue is purified by column        chromatography on silica gel (360 g) and the fractions        containing the desired compound are collected and evaporated in        vacuo to yield        (−)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic        acid tert-butyl ester (4.27 g; yield=85%). 1H-NMR (400 MHz;        DMSO-D6): δ 7.3-7.1 (m, 4H), 5.5 (d, J=5 Hz, 1H), 3.85-3.55 (m,        1H), 3.35-3.25 (m, 1H), 3.25-3.1 (m, 1H), 2.6-2-45 (m, 1H), 2.28        (s, 3H), 1.9-1.4 (m, 7H), 1.36 (s, 9H), 1.13-0.98 (m, 1H).    -   f)        (−)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic        acid tert-butyl ester (4.27 g; 12 mmol) is dissolved in a        solution of 1M HCl in ethylacetate, (240 ml) end stirred at room        temperature for 6 h. After completion of of the hydrolysis (TLC)        the solvent is evaporated in vacuo to yield        (−)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole        hydrochloride (3.39 g; yield=93%) m.p.=181-183° C.    -   g) (−),(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole        hydrochloride (3.38 g; 11.6 mmol) is suspended in CH₂Cl₂ (174        ml), triethylamine (3.6 ml; 25.52 mmol) is added and the mixture        is cooled to 5° C. Methylchloroformate (1.2 ml; 15.08 mmol) is        added dropwise. After completion of the addition, the cooling        bath is removed and the solution stirred for 2 h. The reaction        mixture is diluted with CH₂Cl₂ (250 ml) and washed with brine        (1×50 ml). The aqueous phase is extracted with CH₂Cl₂ (50 ml),        the combined organic phases are dried over Na₂SO₄, filtered and        the solvent evaporated in vacuo. The residue is column        chromatographed on silica gel (240 g), eluent toluene/acetone        9:1 v/v. The fractions containing the desired compound are        collected and evaporated in vacuo to yield 3.39 g        (−)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic        acid methyl ester (yield=90%). M.p.=110-112° C., [α]_(D)=−20.6        (c=1, methanol).

Following the same procedure, the following compounds are obtained:

EXAMPLE 1a(−)-(3aR,4S,7aR)-4-Hydroxy4-m-tolylethynyl-octahydro-indole-1-carboxylicacid ethyl ester

M.p.=118-121° C.

EXAMPLE 1b(−)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-indol-1-yl)-methanone

M.p.=195.5-196.5° C.

EXAMPLE 1c(±)-(3aRS,4SR,7aRS)-4-(3-Chlorophenylethynlyl)-4-hydroxy-octahydro-indole-1-carboxylicacid ethyl ester

1H NMR (400 MHz; CDCl3): 1.27(t, 3H), 1.60-1.80(m, 4H), 1.88-2.11(m,5H), 2.27(m, 1H), 3.38(m, 1H), 3.54(m, 1H), 4.10(m, 2H), 7.22-7.31(m,3H), 7.40(m, 1H).

EXAMPLE 1d(±)-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylicacid ethyl ester

HPLC-MS; 354 (M+Na).

EXAMPLE 1e (3aRS,4SR7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylicacid(S)(tetrahydrofuran-3-yl)ester

ES-MS (+): 356 (M+1).

EXAMPLE 1f(3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylicacid(R)(tetrahydrofuran-3-ester

ES-MS (+): 356 (M+1).

EXAMPLE 1g(3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carboxylicacid-(S)(tetrahydrofuran-3yl)ester

1H NMR (400 MHz CHCl3): 7.39 (s, 1H), 7.25 (m, 3H), 5.27 (m,1H),4.10-3.85 (m, 5H), 3.55 (m, 1H), 3.4 (m, 1H), 2.7 (m, 1H), 2.3 (a,1H), 2.2-1.9 (m, 6H), 1.8-1.0 (m, 3H), 1.07 (m, 1H).

EXAMPLE 1h(±)-(3aRS,4SR,7aRS)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 328.2 [M+1], m.p.=123-124° C.

EXAMPLE 1i(±)-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 332.2, m.p.=115-116° C.

EXAMPLE 1j(±)-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methanesulfonyl-octahydro-indole

NMR (CDCl3): 7.41 (s,1H), 7.30 (m, 3H), 3.93 (m, 1H), 3.57 (m, 1H), 3.35(m, 1H), 2.85 (s,3H), 2.69 (m, 1H), 2.35 (bs,1H), 2.14 (m, 1H), 2.0 (m,1H), 1.90, m,1H), 1.82-1.65 (m, 4H), 1.35 (m, 1H). HPLC: 1 peak, 99%

EXAMPLE 2 (±)-(3aRS,7aRS)-4-Phenylethynyl-2,33a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester and(±)-(3aRS,7aRS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

A solution of 4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylicacid ethyl ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) andphosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40° C. for 4hours. The dark mixture is coded to 0° C. and treated with 1M sodiumhydroxide (5 ml) and then acidified with a 10% aqueous citric addsolution. The mixture is extracted with dichloromethane, the organicextracts are washed with brine, dried over anhydrous magnesium sulfateand evaporated in vacuo. The residue is chromatographed on silica withhexane and diethyl ether (4:1 v/v). The first product containingfractions afforded(±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acidethyl ester (10 mg, 1%) as a yellowish oil. 1H-NMR (400 MHz CDCl3): 7.44(m, 2H), 7.32 (m, 3H), 4.24-3.97 (m, 3H), 3.8 (m, 1H), 3.25 (m, 1H),2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m, 1H), 1.60 (m, 2H),1.28 (t, J=7 Hz, 3H), 1.14 (m, 1H), ES-MS (+): 296.1. After collecting amixture of the two products (475 mg, 50%), the third product containingfractions yielded(±)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400 MHz;CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m, 2H),4.01-3.83 (m, 1H), 3.46(m, 2H), 2.82 (m, 1H), 2.37-1.82 (m, 5H), 1.57(m,1H), 1.27 (t, J=7 Hz, 3H). ES-MS (+): 296.2.

Following the same synthetic procedure the following examples can bemade:

EXAMPLE 2a(±)-(3RS,7aRS)-2,2,2-Trifluoro-1-(4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indol-1-yl)-ethanone

ES-MS (+): 320.3 (M+1), R_(f)=0.62 (TLC silica gel, hexane/ethyl acetate2:1).

EXAMPLE 2b(±)-(RS)-4-m-Tolylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 310.2 (M+1), R_(f)=0.55 (TLC silica gel, hexane/ethyl acetate2:1).

EXAMPLE 2c(±)-(3RS,7aRS)-4-m-Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 310.2 (M+1), R_(f)=0.59 (TLC silica gel, hexane/ethyl acetate2:1).

EXAMPLE 2d(±)-(3RS,7aRS)-4-(4-Chloro-phenylethynyl)-2.3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 330.2 (M+1), R_(f)=0.56 (TLC silica gel, hexane/ethyl acetate2:1).

EXAMPLE 2e(±)-(3RS,7aRS)-4-(2-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 314.2 (M+1), R_(f)=0.42 (TLC silica gel, hexane/ethyl acetate2:1).

EXAMPLE 2f(±)-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 314.2 (M+1).

EXAMPLE 2g(±)-(RS)-4-(3-Fluoro-phenylethenyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 336.2 (M+Na).

EXAMPLE 2h(±)-(3RS,7aRS)-4-(3-Methoxy-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 348.2 (M+Na).

EXAMPLE 2i(±)-(RS)-4-(3-Methoxy-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-carboxylicacid ethyl ester

ES-MS (+): 348.2 (M+Na),

EXAMPLE 3(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-indole-2-carboxylicacid ethyl ester

-   -   a) A solution of 716 g acetic acid        (±)-(3aRS,4RS,7aRS)-2-benzyl-1,3-dioxo-2,3,3a4,7,7a-hexahydro-1H-isoindol-4-yl        ester [CAN 153255-27-7, see J. Chem. Soc. Perkin Trans I (1993),        1925-1929] in 3.5 l tetrahydrofuran is added dropwise to 300 g        lithium aluminum hydride in 3.5 l tetrahydrofuran at 50° C.        Thereafter the mixture is refluxed for 1 h, then cooled to 0°        C., 800 ml water, followed by 300 ml aqueous sodium hydroxide        solution and again 600 ml water is added at max. 15° C. After        filtration about 550 g slightly brown crystallizing oil,        consisting of        (±)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol        is obtained. M.p, 69-71C.    -   b) 1020 g        (±)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol        and 560 g oxalic acid dihydrate are dissolved in 18 l water,        then hydrogenated using 200 g 10% palladium on charcoal catalyst        at 100° C., 100 atm for 16 h. After filtration of the catalyst        the solution is concentrated to a volume of 6 l and 4.5 l        dichloromethane are added, 810 g potassium hydroxide pellets are        added portionwise, then ethyl chloro formate is added dropwise        at a temperature not exceeding 30° C. The reaction mixture is        extracted with dichloromethane, evaporated to yield 827 g        (±)-(3aRS,4SR,7aSR)-4-hydroxy-octahydro-isoindole-2-carboxylic        acid ethyl ester as slightly brown oil; purity by GC: 98.6%.    -   c) To 6.6 g oxalic chloride in 300 tetrahydrofuran at −60° C.        7.4 g dimethylsulfoxide are added, then stirred for 15 min. 10 g        (±)-(3aRS,4SR,7aSR)4-hydroxy-octahydro-isoindole-2-carboxylic        acid ethyl ester in 50 ml tetrahydrofuran is added at −50° C.,        followed by 23 g triethylamine and allowed to warm at rt. The        suspension is filtered, 400 ml ethyl acetate is added to the        filtrate and the mixture washed with 3 times 400 ml water.        Organic phases are dried with sodium sulfate and evaporated        yielding 9.9 g        (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid        ethyl ester as crude brown oil. ES-MS(-): 210 (M−1), RP-HPLC:        single peak.    -   d) 2.1 g (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic        acid ethyl ester in 10 ml tetrahydrofuran is added at −10° C. to        20 ml of 1M lithium phenylacetylide in tetrahydrofuran within 10        min. After 16 h at room temperature 100 ml saturated aqueous        ammonium chloride solution is added, the mixture extracted with        ethyl acetate, solvents dried over sodium sulfate and        evaporated. The product is flash-chromatographed on silica gel        with hexane/ethyl acetate (2:1). 2.2 g        (±)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic        acid ethyl ester are obtained as brown oil ES-MS(+): 314 (M+1),        RP-HPLC: single peak.

Following the same procedure the following compounds are obtained:

EXAMPLE 3a(±)-(3aR,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylicacid ethyl ester

ES-M(+): 328 (M+1), RP-HPLC: single peak.

EXAMPLE 3b(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-carboxylicacid ethyl ester

HPLC-MS: single peak, 350 (M+Na).

EXAMPLE 3c(±)-(3aR,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydro-isoindole-2-carboxylicacid ethyl ester

HPLC-MS.: single peak, 351 (M+Na).

EXAMPLE 3d(±)-(3aR,4RS,7aSR)-4-Hydroxy-4-(3-methoxy-phenylethynyl)-octahydro-isoindole-2-carboxylicacid ethyl ester

ES-MS(+): 344 (M+1), HPLC: single peak.

EXAMPLE 3e (±)-(3aRS,4RS,7aSR)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-isoindole-2-carboxylicacid ethyl ester

ES-MS(+): 332 (M+1), HPLC: single peak.

EXAMPLE 4(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-isoindole-2-carboxylicacid tert-butyl ester

-   -   a) Crude (±)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic        acid tert-butyl ester is prepared in a 4-step procedure without        purification: Starting from        (3aSR,7aRS)-4-oxo-octahydro-isoindole-2-carboxylic acid ethyl        ester: 1) Ketal formation with ethylene glycole in        toluene/p-TsOH. 2) Removal of the ethyl carbamate using KOH in        MeOH in sealed tube at 100° C. 3) Removal of ketal using 4N        aqueous hydrochloric acid in acetone at room temperature. 4)        Formation of the tert.-butyl carbamate using BOC-anhydride,        K₂CO₃, in dichloromethane.    -   b) Reaction to        (±)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic        acid tert-butyl ester as described in Example 3d). ES-MS(+): 342        (M+1), RP-HPLC: single peak.

Following the same procedure, the following compound is obtained:

EXAMPLE 4a(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylicacid tert-butyl ester

ES-MS(+): 356 (M+1), RP-HPLC: single peak.

EXAMPLE 5(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylicacid methyl ester

-   -   a) 1 g of        (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic        acid tert-butyl ester is treated with ca. 1N HCl in ethyl        acetate at room temperature for 18 h, then washed with saturated        sodium hydrogencarbonate solution. The organic phase is dried        over Na2SO4 and evaporated. Purification by prep-HPLC.        (±)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol is        obtained.    -   b) 60 mg of        (±)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol, 25        mg methyl chloroformate and 250 mg polymer-supported H0nig's        base in 5 ml dichloromethane are stirred at room temperature for        18 h, then filtered and evaporated, followed by prep-HPLC        purification to yield        (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic        acid methyl ester. HPLC-MS: 336 (M+Na).

Following the same procedure, the following compounds are obtained:

EXAMPLE 5a(±)-(3aRS,4RS,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-methanone

HPLC-MS: 372 (M+Na).

EXAMPLE 5b(±)-(3aRS,4RS,7aSR)-Cyclopropyl-(4-hydroxy-4-m-tolylethynyl-octahydro-isoindol-1-yl)-methanone

HPLC-MS: 346 (M+1Na).

EXAMPLE 5c(±)-(3aRS,4RS,7aSR)-(4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-yl)-pyridin-3-yl-methanone

HPLC-MS: 361 (M+1), 383 (M+Na).

EXAMPLE 6(±)-((1SR,3SR)-3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamicacid methyl ester and(±)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamicacid methyl ester

-   -   a) To a solution of 3-methylamino-cyclohex-2-wane (1.35 g, 10.8        mmol; CAS 55998-74-8) and triethylamine (4.5 ml, 32.4 mmol)        dichloromethane (20 ml) is added methyl chloroformate (2.5 ml,        32.4 mmol) at 0° C. during 15 minutes. After 45 minutes the        reaction mixture is diluted with dichloromethane and washed        three times with citric acid (10% w/v). The organic phase is        concentrated in vacuo and the residue is treated with K₂CO₃ (3.0        g, 21.6 mmol) in water/methanol (1:1 v/v, 20 ml) for 15 minutes.        The reaction mixture is concentrated in vacuo and the residue        partitioned between water and dichloromethane and after        concentration in vacuo the mixture is chromatographed on silica        gel (100 g) with hexane/ethyl acetate (1:1 v/v) as eluent. The        product methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl        ester is obtained as a pale orange oil. NMR (400 MHz; CDCl₃:        5.68 (s, 1H), 3.79 (s, 3H), 3.20 (s,3H), 2.82 (t, J=6.5 Hz, 2H).        2.39 (t, J=6.5 Hz, 2H), 2.00 (quint., J=6.5 Hz, 2H).    -   b). A solution of methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid        methyl ester (412 mg, 2.2 mmol) in methanol (20 ml) is        hydrogenated with Pd/C (10%, 80 mg, 1 bar). After filtration the        crude product is chromatographed on silica gel (30 g) with        hexane/ethyl acetate 0:1 v/v) as eluent.        Methyl-(3-oxo-cyclohexyl)-carbamic acid methyl ester is obtained        as a colorless oil. NMR (400 MHz; CDCl₃): 4.23 (br, 1H), 3.69        (s, 3H), 2.83 (br, s, 3H), 2.57-2.34 (m, 3H), 2.21 (td, J=14 Hz,        J=6 Hz, 1H), 2.05 (m, 1H), 1.91 (m, 1H), 1.80 (qd, J=12.5 Hz,        J=3.5 Hz, 1H), 1.6 (m, 1H).    -   c) The reaction of methyl-(3-oxo-cyclohexyl)-carbamic acid        methyl ester with lithium m-tolylacetylide is performed as in        example 1. After chromatography on silicagel with hexane/ethyl        acetate (gradient 4:1 to 1:1 v/v) as eluent the title compound        (±)-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic        acid methyl ester (yield 24%) is first eluted (R_(f)=0.62 (TLC        silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)⁺)        followed by        (±)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic        acid methyl ester (yield 50%, R_(f)=0.49 (TLC silica gel,        hexane/ethyl acetate 1:1). HPLC-MS: 324.2 (M+Na)⁺).

Following the same procedure the following compounds are obtained;

EXAMPLE 6a(±)-(1RS,3SR)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamicacid ethyl ester

HPLC-MS: 444.2 (M+Na)⁺.

EXAMPLE 6b(±)-(1RS,3RS)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamicacid ethyl ester.

HPLC-MS: 444.2 (M+Na)⁺.

EXAMPLE 6c(±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethyl-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 368.2 (M+Na)⁺.

EXAMPLE 6d(±)-(1RS,3SR)-(3-Hydroxy-5,5-dimethyl-3-m-tolylethynyl-cyclohexyl)-methyl-carbamicacid methyl ester

HPLC-MS: 352.2 (M+Na)⁺.

EXAMPLE 6e(±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 356.2 (M+Na)⁺.

EXAMPLE 6f(±)-[(1RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 328.2 (M+Na)⁺.

EXAMPLE 6g(±)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 328.2 (M+Na)⁺.

EXAMPLE 6h(±)-[(1RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 340.2 (M+Na)⁺.

EXAMPLE 6i(±)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamicacid methyl ester

HPLC-MS: 340.2 (M+Na)⁺.

EXAMPLE 6j(±)-[(1RS,3RS)-3-(3-Chloro-phenylethynyl-3-hydroxy-cyclohexyl]-methyl-carbamicacid methyl ester

R_(f)=0.31 (TLC silica gel, hexane ethyl acetate 1:1).

EXAMPLE 6k(±)-[(1RS,3SR)-3-(3-Chloro-phenylethynyl)3-hydroxy-cyclohexyl]-methyl-carbamicacid methyl ester

R_(f)=0.22 (TLC silica gel, hexane/ethyl acetate 1:1).

EXAMPLE 6l (±)-(1RS,3RS)-N-(b3-hydroxy-3-m-tolylethynyl-cyclohexyl]-acetamide HPLC-MS: 294.2 (M+Na)EXAMPLE 6m

(±)-(1RS,3SR)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamide

M.p. 152-155° C.

EXAMPLE 6n(±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acidethyl ester

HPLC-MS: 324.2 (M+Na).

EXAMPLE6o (±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamicacid ethyl ester

M.p. 106-107° C.

EXAMPLE 6o(±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl-3-hydroxy-cyclohexyl]-carbamicacid ethyl ester

HPLC-MS: 328.2 (M+Na).

EXAMPLE 6q(±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid ethyl ester

M.p. 121-123° C.

EXAMPLE 6r(±)-(1RS,3RS)-[3-(3-Methoxy-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid ethyl ester

HPLC-MS: 340 2 (M+Na).

EXAMPLE 6s(±)-(1RS,3RS)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamideHPLC-MS: 340.2 (M+Na). EXAMPLE 6t(±)-(1RS,3SR)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide

HPLC-MS: 276.2 (M+1), 298.2 (M+Na),

EXAMPLE 6u(±)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamicacid ethyl ester

HPLC-MS; 340.2 (M+Na).

EXAMPLE 6v(±)-(1RS,3RS)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamideHPLC-MS: 288.2 (M +1), 310.2 (M+11a), EXAMPLE 6w(±)-(1RS,3SR)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide

HPLC-MS: 288.2 (M-1), 310.2 (M+Na).

EXAMPLE 6x(±)-(1RS,3RS)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamicacid tert-butyl ester

HPLC-MS: 368.2 (M+Na).

EXAMPLE 6y(±)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamicacid tert-butyl ester

HPLC-MS: 368.2 (M+Na).

EXAMPLE 6z(±)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acidtert-butyl ester

HPLC-MS: 352.2 (M+Na).

EXAMPLE 6aa(±)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acidtert-butyl ester

HPLC-MS: 352.1 (M+Na).

EXAMPLE 6ab(±)-(1RS,3RS)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid tert-butyl ester

HPLC-MS: 356.2 (M+Na).

EXAMPLE 6ac(±)-(1RS,3SR)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid tert-butyl ester

HPLC-MS: 356.2 (M+Na).

EXAMPLE 6ad(±)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid methyl ester

HPLC-MS: 314.2 (M+Na).

EXAMPLE 6ae(±)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamicacid methyl ester

HPLC-MS: 314.2 (M+Na).

EXAMPLE 7 (±)-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethylester and (±)-3-phenylethyl-cyclohex-3-enyl)-carbamic acid ethyl ester

100 mg (0.35 mmol) (3-hydroxy-3-phenylethynyl-cyclohexyl)-carbamic acidethyl ester (diasteromeric mixture 2) in 15 mL toluene are treated with10 mg p-toluene sulfonic acid and stirred 6 hours at 120”, After coolingand addition of 50 ml ethyl acetate, the product is washed with watercontaining a small amount of sodium bicarbonate, and saline. The organicphase is dried with sodium sulfate, concentrated and columnchromatographed using a 3:1 mixture of petroleum ether and ethylacetate. The first product to come out of the column is(3-phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester (yield,23%), followed by (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethylester (yield: 48%) Racemate 1: ¹H-NMR (400 MHz) delta 7.41 (m, 2H); 7.30(m, 3H); 6.04 (a, 1H); 4.63 (broad s, 1H); 4.35 (broad s, 1H): 4.10 (q,2H): 2.20 (a, 2H); 1.90 (m, 1H); 1.70, (m, 2H); 1.50 (m, 1H); 1.23 (t,3H).

Racemate 2; ¹H-NMR (400 MHz); delta 7.40 (m, 2H); 7.30 (m, 3H); 6.19 (s,1H); 4.68 (broad s, 1H); 4.10 (q, 2H); 3.92 (broad s, 1H); 2.81 (d, 1H);2.28 (broad a, 2H); 2.12, 1.85, 1.59 (3 m, 3H); 1.23 (t, 3H).

EXAMPLE 8 (±)-Methyl-(3-phenylethynyl-cyclohex-3-enyl)-carbamic acidethyl ester

22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethylester are dissolved in 2 ml DMF and 1 THF. 8 mg (0.165 mmol) of a 60%dispersion of NaH in oil is added and the mixture stirred under argonfor 90 minutes at room temperature. The reaction mixture is cooled to0°, and 16 microliters Mel in 0.5 ml THF are added dropwise. Afterstirring one hour at room temperature, the reaction mixture is cooled to0° again, ice is added and the crude product extracted with ethylacetate, washed with water and saline, dried with sodium sulfate andcolumn chromatographed using a 4:1 mixture of petroleum ether and ethylacetate. Yield: 43%.

¹H-NMR (400 MHz): delta 7.40 (m, 2H); 7.30 (m, 3H); 6.18 (s, 1H); 4.22(broad m, 1H); 4.15 (q, 2H); 2.8 (broad s, 3H); 2.35 (broad s, 4H);1.80-1.60 (m, 1H): 1.15 (t, 3H).

EXAMPLE 9(±)-(4aRS,5RS,8aSR)-5-Hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylicacid ethyl ester

-   -   a) To the mixture of (±)-(4aRS,8aSR)-octahydro-quinolin-5-one        oxalate (1.50 g, 8.17 mmol), toluene (5 ml) and water (5 ml) is        added solid potassium carbonate. After stirring for a few        minutes ethyl chloroformate (0.71 ml, 7.4 mmol) is added and the        reaction mixture is then stirred at room temperature for 3        hours. The organic phase is separated and the aqueous phase        extracted with dichloromethane (3×10 ml). The combined organic        phases are dried over magnesium sulphate and concentrated in        vacuo to yield 1.22 g (88%) of        (±)-(4aRS,8aSR)-5-Oxo-octahydro-quinoline-1-carboxylic acid        ethyl ester. 1H NMR (400 MHz; CDCl3): 1.28 (t, 3H), 1.40 1.70        (m, 3H), 1.72-1.90 (m, 1H), 2.0-2.20 (m, 3H), 2.30-2.48 (m, 3H),        2.55 (td, 1H), 3.32 (td, 1H), 3.50 (m, 2H), 4.12 (q, 2H).    -   b) To a solution of        (±)-(4aRS,8aSR)-5-oxo-octahydro-quinoline-1-carboxylic acid        ethyl ester (0.372 g, 1.65 mmol) in THF (15 ml) is added a        solution of lithium phenylacetylide in THF (3.30 ml, 3.30 mmol;        1.0M solution in THF) at −50 C. The reaction mixture is then        stirred for 1.5 hours at -50C and then allowed to warm to room        temperature. The reaction mixture is diluted with diethyl ether        (100 ml), washed with saturated sodium bicarbonate solution        (2×10 ml), water (10 ml), dried over magnesium sulfate and then        concentrated in vacuo. Purification of the crude product        (0.860 g) using silica gel chromatography (ethylacetate/hexane        1:3 v/v) give        (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylic        acid ethyl ester.(0.144 g, 26.7%).

Following the same procedure the following compounds are obtained:

EXAMPLE 9a(±)-1(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone

NMR (DMSO-D6, 500 MHz): 7.84 (s,1H), 7.45 (m, 4H), 6.95 (d,1H), 6.63(d,1H), 5.51 (s,1H), 4.03 (m, 1H), 3.94 (m, 1H), 3.32 (m, 1H), 2.06 (m,1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.94 (m, 1H), 1.85 (m, 1H), 1.74(m.2H), 1.71 (m, 1H), 1.60 (m, 1H), 1.50 (m, 1H), 1.41 (m, 1H).

EXAMPLE 9b(±)-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl-5-hydroxy-octahydro-quinolin-1-yl]-furan-2-yl-methanone

NMR (DMSO-D6, 500 MHz): 7.83 (s,1H), 7.43 (m, 4H), 6.95 (d,1H), 6.62 (m,1H), 5.77 (s,1H), 3.99 (m, 1H), 3.90 (m, 1H), 3.31 (m, 1H), 2.12 (m,1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 1.83 (m, 1H), 1.77 (m,1H), 1.66 (m, 1H), 1.59 (m, 2H), 1.46 (m, 1H), 1.22 (m, 1H).

EXAMPLE 9c(±)-(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylicacid tert-butyl ester

NMR (CDCl3): 7.42 (d, J=1.1 Hz, 1H), 7.32 (m, 3H), 3.55 (m, 1H), 3.48(m, 1H), 3.10 (m, 1H), 2.08 (m, 3H), 1.90 (m, 1H), 1.8-1.6 (m, 7H), 1.46(s, 9H), 1.38 (m, 1H).

EXAMPLE 9d(±)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-morpholin-4yl-methanone

LC-MS, M+1=403.1

EXAMPLE 9e(±)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-(4-methyl-piperazin-1yl)-methanone

LC-MS, M+1=416.2

EXAMPLE 10(±)-(4aRS,5RS,8aRS)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylicacid ethyl ester and(±)-(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylicacid ethyl ester

-   -   a) To a solution of trimethylsilylacetylene (1.54 ml, 10.8 mmol)        in THF (10 ml), is added a solution of n-butyllithium in hexane        (6.75 ml, 10.8 mmol; 1.6M in hexane) at 0°. The reaction mixture        is stirred at 0° C. for 45 minutes and then at room temperature        for 20 hours. The reaction mixture is diluted with diethyl ether        (100 ml), washed with saturated sodium bicarbonate solution        (2×10 ml), dried over magnesium sulfate and concentrated in        vacuo. Purification of the crude product (2.0 g) using silica        gel chromatography (ethylacetate/hexane gradient 0-40% v/v) give        (±)-(4aRS,5RS,8aSR)-5-hydroxy-5-trimethylsilanylettlynyl-octahydro-quinoline-1-carboxylic        acid ethyl ester, (1.48, 84%); 1H NMR (400 MHz; CDCl3): 1H NMR        0.1 (s-overlap, 9H), 1.05 (t, 3H), 1.10-1.30 (m, 2H), 1.30-1.60        (m, 6H), 1.60-1.95 (m, 4H), 2.80-3.0 (m, 1H), 3.25-3.50(m, 1H),        3.50-3.65 (m, 1H), 3.95(m, 2H). Further chromatographic        fractions all contain variable mixtures of        (±)-(4aRS,5RS,8a9R)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic        acid ethyl ester and        (±)-(4aRS,5SR,8a8R)-6-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic        acid ethyl ester.        -   b) A mixture (approximately 5:1) of            (±)-(4aRS,5RS,8SR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic            acid ethyl ester and            (±)-(4aRS,5SR,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quinoline-1-carboxylic            acid ethyl ester (0.272 g, 0.84 mmol),            1-bromo-3-chloro-benzene (0.161 g, 0.84 mmol),            copper(I)iodide (0.016 g, 0.093 mmol), triphenylphosphine            (0.02 g,0.074 mmol), potassium carbonate (0.127 g, 0.02            mmol), palladium on carbon (10%) (10 mg) in dimethoxyethane            (2 ml) and water (1 ml) are combined together and heated at            55° C. for 24 hours under argon atmosphere. The reaction            mixture is cooled to room temperature, filtered through            celite, washed with diethyl ether and concentrated in in            vacuo to yield a crude oil The crude di (0.181 g) is            purified using silica gel chromatography (ethylacetate r            hexane gradient 0-30%) and fractions containing the desired            compounds are collected and evaporated in vacuo to yield the            first product            (±)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic            acid ethyl ester. (140 mg, 46%). ¹H NMR (400 MHz; CDCl3);            1.28 (t, 3H), 1.2 8-1.50 (m, 2H), 1.50-2.00 (m, 2.0-2.20 (m,            3H), 3.08 (m, 1H) 3.55 (tm, 1H), 3.80 (m, 1H), 4.15 (q,            2H),7.24-7.40(m, 4H) and the second product            (±)-(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1-carboxylic            acid ethyl ester (30 mg, 10%), ¹H NMR (400 MHz; CDCI3): 1.29            (t, 3H), 1.41-1.58(m, 2H), 1.58-2.00(m, 8H), 2.08-2.18 (m,            2H), 3.16 (m, 1H), 3.61 (m, 1H), 3.70 (m, 1H), 4.10 (m,            2H),7.16-7.30(m, 4H).

Following the same procedure the following compounds are obtained:

EXAMPLE 10a(±)-(4aRS,5SR,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-carboxylicacid ethyl ester

¹H NMR (400 MHz; CDCl3): 1.25 (t, 3H), 1.39-1.56 (m, 2H), 1.56-1.98 (m,8H), 1.98-2.23 (m, 2H) 2.35 (a, 3H), 3.15 (m, 1H), 3.55-3.79 (m, 2H),4.04-4.20 (m, 2H),7.10 (m, 1H)7.15-7.25 (m, 3H)

EXAMPLE 10b(±)-(4aRS.,5RS,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-carboxylicacid ethyl ester

¹H NMR (400 MHz CDCl3): 1.25 (t, 3H), 1.30-1.50 (m, 2H), 1.56-2.20 (m,8H), 220-2.44 (m, 3H), 2.85-3.19(m, 1H), 3.54-3.63 (m, 1H), 3.69-3.84(m, 1H), 4.07-4.19 (m, 2H),7.05-7.27 (m, 4H).

EXAMPLE 11(±)-Ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamicacid methyl ester and(±)-ethyl-((1SR,3RS)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamicacid methyl ester

-   -   a) To a solution of 3-methoxy-cyclopent-2-enone (800 mg, 7.13        mmol) in 30 ml of an ethylamine solution to THF, (2.0 M, 60        mmol) acetic acid (200 μl) is added and the mixture stirred at        70 ° C. for 2 h. The reaction mixture is concentrated in vacuo        and the residue is filtered through silica gel with acetone. The        resulting solid is crystallized from dichloromethane/other to        yield 3-ethylamino-cyclopent-2-enone as white crystals, m.p.        136-138.5*C.    -   b) To a solution of 3-ethylamino-cyclopent-2-enone (500 mg, 4        mmol) in 4 ml THF and 1 ml DMF, sodium hydride (12 mmol) is        added. After stirring the reaction mixture for 20 minutes at        room temperature, methyl chloroformate (615 μl, 8 mmol) is        added. After stirring for 16 minutes, the reaction mixture is        quenched with saturated aqueous ammonium chloride solution and        concentrated in vacuo. The residue is partitioned between brine        and dichloromethane. The organic extracts are chromatographed on        silica gel (30 g) with dichloromethane/methanol (95:5 v/v) as        eluent to afford ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid        methyl ester which is crystallized from dichloromethane/ether,        m.p. 68-68° C.    -   c) Ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid methyl ester        (400 mg, 2.16 mmol) is hydrogenated in methanol with Pd/C (10%,        80 mg) to yield (±)-ethyl-((R,S)-3-oxo-cyclophentyl)-carbamic        acid methyl ester as a yellowish oil.    -   d) The reaction of (±)-ethyl-(R,S)-3-oxo-cyclopentyl)-carbamic        acid methyl ester with lithium m-tolylacetylide is performed as        in example 1. After chromatography on silicagel with        hexane/acetone (5:1 v/v) as eluent, the title compound        (±)-ethyl-((1SR,3RS)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic        acid methyl ester is first eluted [R_(f)=0.48 (TLC silica gel,        hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na)⁺] followed by        (±)-ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic        acid methyl ester [R_(f)=0.39 (TLC silica gel, hexane/ethyl        acetate 1:1), HPLC-MS: 324.2 (M+Na)⁺], both as pale yellow oils.

1. A compound of formula I

wherein m is 0 or 1, n is 0 or 1 and A is hydroxy X is hydrogen and Y ishydrogen, or A forms a single bond with X or with Y; R₀ is hydrogen.(C₁₋₄)alkyl, (C₁₋₄)alkoxy, trifluoromethyl, halogen, cyano, nitro,—COOR₁ wherein R₁ is (C₁₋₄)alkyl or —COR₂ wherein R₂ is hydrogen or(C₁₋₄)alkyl, and R is —COR₃, —COOR₃, —CONR₄R₅ or —SO₂R₆, wherein R₃ is(C₁₋₄)alkyl, (C₃₋₇)cycloalkyl or optionally substituted phenyl,2-pyridyl or 2-thienyl, R₄ and R₅, independently, are hydrogen or(C₁₋₄)alkyl and R₃ is (C₁₋₄alkyl, (C₃₋₇)cycloalkyl or optionallysubstituted phenyl, R′ is hydrogen or (C₁₋₄)alkyl and R″ is hydrogen or(C₁₋₄)alkyl, or R′ and R″ together form a group —CH₂—(CH₂)_(p)— whereinp is 0, 1 or 2, in which case one of n and p is different from 0, withthe proviso that R₀ is different from hydrogen, trifluoromethyl andmethoxy when m is 1, n is 0, A is hydroxy, X and Y are both hydrogen, Ris COOEt and R′ and R″ together form a group —(CH₂)₂—, in free base oracid addition salt form.